RAS Mutations and Colorectal Cancer Liver Metastases

Gene mutations may have implications for local therapy for liver
metastases from colorectal cancer

BY Joe Munch

A scatter plot of 25 liver metastases in 22 patients who had local tumor
progression (LTP) after percutaneous ablation shows that lesions with
mutant RAS (blue crosses) had shorter times to LTP and were smaller than
lesions with wild-type RAS (red circles). RAS mutations were associated
with worse 3-year LTP-free survival rates in both univariable and
multivariable analyses; tumor size of 2 cm or more was associated with
lower 3-year LTP-free survival rates in univariable, but not
multivariable, analysis (data not shown). Image used with permission
from Br J Surg, 2017;104:760–768.

Mutations of the RAS oncogene are known to predict poor overall and recurrence-free survival for patients who receive systemic therapy for colorectal cancer liver metastases. Now, the findings of recent studies from The University of Texas MD Anderson Cancer Center suggest that RAS mutations affect the outcome of local therapy for these metastases.

“This goes beyond just predicting survival,” said Jean-Nicolas Vauthey, M.D., a professor and chief of the Hepato-Pancreato-Biliary Surgery Section in the Department of Surgical Oncology.

Noting that RAS mutations have long been known to render EGFR (epidermal growth factor receptor)-targeting therapies such as cetuximab and panitumumab ineffective, Dr. Vauthey said, “We need to understand that RAS mutation status has treatment implications besides targeted therapy selection. We’re showing for the first time that RAS mutation status needs to be considered when making local treatment decisions for patients with colorectal cancer liver metastases.”

Implications for surgery

For many patients who have colorectal cancer liver metastases and either no evidence of disease outside the liver or extrahepatic disease considered to be completely resectable, neoadjuvant chemotherapy followed by hepatectomy offers the best chance at a cure. Whether such surgery is successful is determined in part by assessing the surgical margins surrounding the resected tumors—negative margins indicate success, whereas positive margins indicate an increased risk for recurrence.

Dr. Bruno Odisio

To achieve histologically negative surgical margins in patients with colorectal cancer liver metastases, surgeons have traditionally aimed for gross resection margins of 10 mm. However, the findings of a recent study led by Dr. Vauthey may change this recommendation for some patients.

For their study, Dr. Vauthey and his colleagues reviewed the cases of 633 patients who underwent potentially curative resection of colorectal cancer liver metastases using traditional 10-mm resection margins. RAS mutations were found in metastatic tumors removed from 229 of these patients.

Of the 633 patients, 225 developed a liver-first recurrence after resection of the liver metastases. “Among patients whose disease recurred in the liver after resection, the median tumor-free margins on pathological examination were much narrower in patients with RAS mutations (4 mm) than in patients without RAS mutations (7 mm),” Dr. Vauthey said. “We also found that patients with mutant RAS had more than double the rate of microscopically positive margins than patients with wild-type RAS did.”

In fact, RAS mutation and carcinoembryonic antigen levels of 4.5 ng/mL or more were the only independent predictors of positive margins.

“Our findings suggest that tumors with RAS mutations have a different phenotype. The morphology of the tumor may be different, or there might be micrometastases around the tumor that we don’t see as we’re doing our resection,” Dr. Vauthey said. “The practical implication of these findings is that we are now aiming for wider gross resection margins—15 mm instead of 10 mm—when we resect colorectal cancer liver metastases in patients with RAS mutations or unknown RAS status because we think it will be beneficial for the patient.”

Implications for ablation

Patients who have colorectal cancer liver metastases that are not amenable to surgery or who cannot undergo surgery for other reasons may undergo image-guided percutaneous ablation of the lesions. Bruno Odisio, M.D., an assistant professor in the Department of Interventional Radiology, was the first author on a recent study to determine whether RAS mutations—already found to be associated with worse preoperative chemotherapy responses, worse survival outcomes, and now narrower tumor-free margins in patients with colorectal cancer liver metastases—might also be related to outcomes of liver ablation.

In the study, Dr. Odisio and his colleagues (including Dr. Vauthey, the study’s senior author) looked at the cases of 92 colorectal cancer patients with known RAS mutation status who underwent percutaneous ablation of 137 liver metastases. Three years after ablation, the rate of local tumor progression (i.e., recurrence at the ablated tumor site) in the patients whose tumors had mutant RAS (39%) was significantly higher than that of the patients with wild-type RAS (14%).

Patients with mutant RAS also had a significantly worse 3-year overall survival rate than patients with wild-type RAS did. The patients with mutant RAS also tended to have disease recurrence much earlier. Mutant RAS and an ablation margin of less than 5 mm were independent predictors of worse local tumor progression–free survival.

“Essentially, patients with RAS mutations have a more aggressive phenotype with a more invasive and migratory tumor biology,” Dr. Odisio said. “So maybe what we’re seeing on computed tomography or magnetic resonance imaging during ablation doesn’t really correlate with what’s happening at the microscopic level.”

Dr. Jean-Nicolas Vauthey

Their findings prompted Dr. Odisio and his colleagues to study whether enlarging the ablation area for patients with RAS mutations decreases recurrence. In this recently completed study, which has not yet been published, the researchers found that the rates of recurrence following percutaneous ablation of colorectal cancer liver metastases were significantly lower for tumors in which the ablation margin was 10 mm or wider than for tumors in which the ablation margin was less than 10 mm. However, regardless of ablation margins, patients with RAS mutations had a significantly higher rate of recurrence after ablation than did those with wild-type RAS.

Dr. Odisio noted that the studies’ findings should be interpreted with care. “The fact that a patient has mutant RAS doesn’t mean that the patient has a contraindication to ablation. It just means that the outcomes we can expect for that patient are not going to be as good as those for a patient without the mutation,” he said. “This further understanding of the patient’s tumor biology helps us to have a more tailored conversation in the clinic. We shouldn’t refrain from offering ablation to patients with RAS mutations, but—similarly to surgery—we need to aim for wider ablation margins in order to reduce the rates of local recurrence.” However, Dr. Odisio added, larger ablations are not always possible in patients with large tumors near critical structures, and other treatments may be more appropriate for such patients.

Ongoing efforts

Drs. Vauthey and Odisio are spearheading other efforts to better understand the development of colorectal cancer liver metastases and improve patient outcomes. For example, Dr. Odisio is looking at the possibility of using circulating tumor DNA, which is released into the bloodstream by dying tumor cells, to determine the completeness of ablation. And Dr. Vauthey is investigating the relationship between RAS mutation status and micrometastasis.

“We’re collecting surgical specimens to compare the rate of micrometastasis between RAS mutant tumors and RAS wild-type tumors,” Dr. Vauthey said. “We’re also using next-generation sequencing to study all the other mutations in colorectal cancer that might have a bearing on treatment decisions.”

In the meantime, Dr. Vauthey said, “We are now in an era in which knowing the RAS mutation status could change the way we treat patients, and we may be able to change their outcomes by improving local therapy.”